Multidimensional Tunability of Nucleic Acids Enables Sensing over Unknown Backgrounds.

A longstanding challenge in quantitative analysis is the relationship between a sensor's dynamic range and a background: the response range must align with the target's background value. If this condition is not met, a reliable measurement is impossible. The requirement is especially critical for sensing systems displaying sharp responses. In this work, we have solved the problem of response range/background misalignment via design of sensing systems that adjust their response to actual unknown backgrounds. The sensing systems are based on nucleic acid scaffolds: due to an intrinsic trait of multidimensional tunability, the sensors can assess the actual background and adjust response range accordingly. We established a general methodology and demonstrated, as a proof-of-concept, a practically meaningful example of detecting very small changes in proton concentrations over unknown aqueous backgrounds using a DNA i-motif sensor. Owing to multidimensional tunability of a DNA i-motif, this sensor could reliably measure changes in proton concentration that are 3 orders of magnitude below currently available methodologies.